The long term goal of this proposal is to test the efficacy of OV-ChaseM virotherapy in combination with anti-CTLA-4 T-cell targeted immunotherapy for breast cancer brain metastases (BM). With a dismal one and two year survival of 20% and 2%, respectively, the development of novel therapeutic modalities is critical for BM. OV-ChaseM is a second generation oncolytic virus that expresses the Chondroitinase ABC (Chase), an enzyme that degrades the extra-cellular matrix. Anti-CTLA-4 is a monoclonal antibody directed against the CTLA-4 inhibitory receptor on T lymphocytes. Using murine models of brain cancer BM, we aim to characterize the anti-tumor immune responses evoked by both individual and combinatorial therapy. We hypothesize that Chondroitinase expression by OV-ChaseM will facilitate the influx of immune cells into the tumor stroma and alleviate microglia suppression. Here, activated microglia can then uptake virally infected cells, present tumor antigens and promote an anti-tumor microenvironment. This, in turn, will enhance T cell anti-tumor responses following anti-CTLA-4 blockade and result in overt immune cell activation and enhanced anti-tumor efficacy, as compared to controls. Overall, we aim to broaden the scope of treatment for brain cancer patients and provide pre-clinical evidence for individual and combinatory therapeutic regiments that may be implemented in the clinic.